To withstand environmental onslaught, biological systems mount global programs to coordinate the induction of protection and repair mechanisms. This proposal poses the hypothesis that the transcriptional networks underlying such responses to diverse stressors are interrelated. Halobacterium, a halophilic archaeon, has been chosen as a model for this study because it routinely negotiates an array of adverse conditions in its extreme environment, including anoxia, metal stress, and radiation damage. This proposal will investigate the inter-relationship of these responses using global approaches. Given that basal genetic information processing pathways in Halobacterium are mediated by eukaryotic-like proteins, findings from this study will have a direct impact on understanding how complex eukaryotic organisms elicit orthogonal responses in disease-perturbed or infection states. Specifically, I will (1) Characterize key transcriptional regulators responsible for mediating responses to fluctuating oxygen concentrations and identify regulons under their direct and indirect control; (2) Through statistical analysis of integrated datasets, evaluate the extent of cross-regulation of the anoxic response with other environmental perturbations; (3) Experimentally test new hypotheses generated by statistical analysis. These proposed experiments are expected to result in a transcriptional network model that addresses how organisms maintain homeostasis despite stress. [unreadable] [unreadable] [unreadable]